Recent clinical studies demonstrate that depression, as well as other psychiatric illnesses can result in a reduce in the volume and function of the hippocampus Pre-clinical studies in rodents in rodents and non- human primates demonstrate that stress can result in morphological alterations of hippocampal neurons, including atrophy and reduced cell proliferation. Stress is also reported to decrease the expression of brain derived neurotrophic factor Although hippocampus is only one of several brain regions implicated in depression, the structural alterations of hippocampus could be related to certain cognitive and vegetative abnormalities in depressed patients. These findings also raise the possibility that the therapeutic action of anti-depressants could occur, in part, via reversal or blockade of these alterations. This hypothesis is supported by our recent studies demonstrated that anti- depressant treatment increases neurogenesis in adult rodent hippocampus. This effect is dependent on chronic administration and is observed with different classes of antidepressants , suggesting that increased neurogenesis is a common action of this type of medication. Preliminary studies also demonstrate that anti-depressant administration blocks the down-regulation of neurogenesis that is caused by stress. The focus of the current application is to determine the molecular mechanisms that mediate the effect of anti-depressants on adult neurogenesis Our previous studies, supported by this grant, demonstrated that anti-depressants up-regulate the cAMP response element binding protein (CREB), a transcription factor implicated in cellular plasticity, and brain derived neurotrophic factor. We will use a combination of pharmacological and mutant mouse models to study the role of CREB and BDNF in adult neurogenesis and in the response to antidepressant treatment. Preliminary studies demonstrate that administration of a drug which blocks cAMP metabolism (rolipram) increases, while over- expression of a dominant negative mutant of CREB decreases, neurogenesis in adult hippocampus. We will also examine additional gene targets of CREB that could influence the differentiation and survival of newborn cells in the adult hippocampus. Finally, studies will be conducted to examine the relationship between adult neurogenesis and behavior responses to anti-depressant treatment. These studies will provide new insight on the molecular mechanisms that control neurogenesis in adult hippocampus and of the role of these pathways in the action of anti-depressant treatment.